Intestine‐Specific Overexpression of Carboxylesterase 2c Protects Mice From Diet‐Induced Liver Steatosis and Obesity

Abstract

Murine hepatic carboxylesterase 2c (<i>Ces2c</i>) and the presumed human ortholog carboxylesterase 2 (<i>CES2</i>) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that <i>Ces2c</i> hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, <i>Ces2c</i>/<i>CES2</i> is most abundantly expressed in the intestine, indicating a role of <i>Ces2c</i>/<i>CES2</i> in intestinal TG metabolism. Here we show that <i>Ces2c</i> is an important enzyme in intestinal lipid metabolism in mice. Intestine-specific <i>Ces2c</i> overexpression (Ces2c^int) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high-fat diet-fed Ces2c^int mice were resistant to excessive diet-induced weight gain and adipose tissue expansion. Notably, intestinal <i>Ces2c</i> overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2c^int mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that <i>Ces2c</i> is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re-esterification. Consequently, the increased availability of MGs and DGs for re-esterification and primordial apolipoprotein B₄₈ particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. <i>Conclusion:</i> This study suggests a critical role for Ces2c in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet-induced weight gain during metabolic stress.